
Go van Dam: The enormous potential of nuclear imaging for drug development
Go van Dam: The enormous potential of nuclear imaging for drug development
Nuclear imaging for diagnosing patients has become indispensable in hospitals. Diagnostic, three-dimensional images can be made by coupling a radionuclide to a substance called a tracer that binds to the tissue of interest. This same principle can be used to track new drugs in the development stage in the body to see if they reach the desired site. Go van Dam of TRACER, a Clinical Research Organization (CRO) specializing in molecular imaging in drug development, talks in this column about the enormous potential this has. To understand its utility, it first addresses the problem of the current method of drug development.
The way we do clinical research can no longer be done like this
The average success rate, that is, drugs that successfully reach the market after about 10 years of clinical trials, is around 10%. So this means that 90% of drugs, and the research associated with them, end up doing nothing for patients. What’s more, the cost of the failed studies must mostly be factored into the price of drugs that do come to market successfully. That’s just talking about the financial costs. The burden this method of clinical research has on participants, the time it takes from medical specialists, and the amount of animal testing required; raises the question of whether this is still justifiable and whether it could not be done smarter.
Where does this problem come from?
Simply put, drug research is very complex. Something that works in a laboratory setting may work very differently in the human body. Early-stage nuclear imaging of the radiolabeled drug in development could partially close this knowledge gap. There is also the sequence in which drugs are developed.
The current order of drug testing
After a preclinical course, including animal testing, of 1-6 years on average, a clinical trial can begin. Clinical indicates that it is being tested on humans for the first time. First, a drug is tested for safety and toxicity at different doses; this falls under phase 1. A goal here is to determine the maximum tolerable dose. This testing is done with healthy volunteers and in some cases with patients. In the next phase, phase 2, the drug is tested for initial efficacy in patients.
Why does research on new drugs fail?
Research on the reason for failure based on analysis of clinical trials between 2010 – 2017 [1] indicates that 40-50% fail based on lack of efficacy, 30% fail based on excessive toxicity, and 20-25% fail for other reasons. Another study [2], based on AstraZeneca’s pipeline over the period 2005-2010 endorses this. In phase 1, 62% failed on safety and in phase 2a and 2b, 57% and 88%, respectively, failed on efficacy. Only 15% of drugs in development went from phase 2 to phase 3. Effectiveness is the biggest reason for failure, but this is tested only after years of large-scale preclinical and clinical trials for safety. It sounds logical, preclinical first before research in humans, and then research in humans focused on safety as a stepping stone to research on efficacy. But, is this really that logical?
The role of nuclear imaging for drug development
The major advantage of nuclear imaging is that only a very low dose is needed to obtain a detailed picture of biodistribution. Radionuclides can be attached to almost any substance as a label, and with the right labeling strategy, the action of the substance will not be affected. These features mean that nuclear imaging has a major role to play in the early stages of drug development.
Fastest in-patient medical research
Below TRACER’s logo is the phrase: “Fastest in-human,” but actually this could have read “Fastest in-patient.” TRACER uses a method approved by the umbrella authorities European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA), among others. Namely, testing drugs in a microdose in patients, also known as phase 0. This type of research can take place much more quickly and can push forward the timeline of initial research in patients-instead of healthy volunteers who do not have the condition-years.
Drug research with microdosing
Microdosing is so low in concentration that no pharmacological effect is to be expected and can be done safely. Thus, a microdose is considered safe but is too low a quantity to measure a therapeutic effect. Thus, it will not suddenly improve the patient. So how can data from this type of study still be of value? This is where nuclear imaging shows its value.
TRACER pairs radioactive substance with new drug
TRACER will first pair the new drug with a radionuclide and make the drug suitable for imaging. The patient is given this drug in microdoses. One or more scans can then be used to see exactly where the drug is in the body. Moreover, the amount of radiation from the radionuclide can be used to calculate to what extent the drug is present in which tissue, and dosimetry can follow on the basis of this data. With this, the potential for toxicity (off-target), as in a phase 1 study, and the potential for efficacy (on-target), as in a phase 2 study, can be estimated more objectively.
What are differences from the traditional method?
One major difference is that the molecular imaging studies with the labeled drug take place in patients and not in healthy volunteers. This is important, as the effect can only really be reliably demonstrated if the disease is actually present. Moreover, a patient with a particular disease may have different pharmacokinetics compared to a healthy volunteer. Another major difference is the timing of this study. A microdose study can already take place after a limited toxicity study – a so-called single-dose extended toxicity study in rats or mice.
Go/no-go decision
Is the result of the microdosing study in patients positive, i.e. favorable biodistribution with specific disease-targeting and no worrying off-targeting (uptake into organs and healthy cells)? Then the next phase of clinical trials can be initiated with reliable data from this earlier study, data that otherwise would not have been available. Does the phase 0 imaging study reveal that the labeled drug does not reach the right site, or does the biodistribution and dosimetry calculation show an unsafely high amount in healthy tissue? If the result is negative, i.e., no specific targeting or nonspecific uptake in healthy tissues and ditto risk of off-target toxicity, an adjustment to the drug may be necessary before proceeding. Optionally, further clinical trials may be discontinued.
More participants for promising drug research
Another previously unmentioned reason where drug research fails is failure to achieve the right number of participants. An analysis [3] of phase 2 and 3 studies, that is, studies with patients, showed that 19% of the studies failed or ended with too few participants. By allowing only studies that are promising in phase 0 to proceed to phase 1-3, there are fewer studies, resulting in more potential patients per study. At TRACER, we also find that hospitals sometimes run multiple studies targeting the same type of patients. Especially in research into infrequent diseases, this can lead to delays.
Innovation opportunities for pharmaceutical companies and governments
The method offered by TRACER, namely conducting early clinical research, fits entirely within the framework set by the government, such as reducing animal research and keeping healthcare affordable. It also fits within the wishes of pharmaceutical companies and researchers to gain more knowledge of a new drug in order to make subsequent clinical trials smarter, cheaper and above all more effective. This leaves the question, why is this not yet the standard order of clinical trials, i.e. phase 0 followed by 1, 2, 3? This is where we think the government has an important role to play. Regulatory organizations like the EMA and FDA could, in our view, do more to make this type of research a requirement before moving forward, supported from the pharmacological and medical professions.
About Go van Dam
Prof. Go van Dam is co-founder of TRACER CRO and a surgeon-oncologist and Professor of Surgery at the University of Groningen, trained at Harvard, the Mayo Clinic and NCI. He is a pioneer in optical imaging with pioneering research to his credit. He published the 1st human application of targeted fluorescence imaging in 2011 (Nature Medicine) and has published more than 140 articles on especially the clinical translation of innovative targeted optical molecular imaging. More recently, he published on the importance of standardization for validation of clinical fluorescence imaging studies toward an industry standard.
Sources:
- https://pmc.ncbi.nlm.nih.gov/articles/PMC9293739/
- https://pubmed.ncbi.nlm.nih.gov/24833294/
- https://journals.sagepub.com/doi/10.1177/1740774514558307